The Neurocritic

Thursday, July 31, 2014

UPDATE (Aug 6 2014): This story has spun entirely out of control, with breathless coverage at The Daily Dot and Jezebel. Today the hapless first author told NBC News: "No, at this point Twitter psychosis is not 'real.'"

And no, a woman was notcommitted to psychiatric hospital with ‛Twitter psychosis’! However, the general confusion created by the ensuing media circus might be what the authors were trying to get at...

The creation of the category “Twitter Psychosis" tells us more about the culture of contemporary psychiatry than it does about the purported dangers of social media overuse. Can Twitter really “cause” psychotic symptoms in predisposed individuals? Or is Twitter merely the latest technical innovation that influences “the form, origin and content of delusional beliefs” (Bell et al., 2005)? Twitter as the new telephone tower, radio waves, microchip implant or personal TV show, if you will.

The authors report the development of psychosis in a young woman coinciding with excessive use of the online communication system Twitter and the results of an experimental account to argue that Twitter may have a high potential to induce psychosis in predisposed users.

The authors presented the case of a 31 year old woman who was hospitalized for intensive suicidal thoughts and compulsions. She had no previous history of psychiatric illness and denied current hallucinations.1 Her friends and family said the symptoms began about 8 months earlier. Approximately 4 months prior to that she started using Twitter “excessively” (defined as “several hours a day reading and writing messages, neglecting her social relationships and, sometimes, even meals and regular sleeping hours”).2 At some point she came to believe that a famous actor was communicating to her personally (a common delusion), and to see hidden symbolic messages in Tweets:

During the next couple of weeks, Mrs. C increasingly felt that the messages of other users were “meant in a symbolic way” and that she had to react to these “tasks” in a certain manner. After approximately 2 months, she started to discover the same symbols in her real-world environment. She then started to feel that there “must be some organization behind these tasks” and started to suspect a sect, pointing to the development of systematized paranoid delusion.

None of this really seems like a Distinct Syndrome, and I doubt it's even a Rare Variation any more. The authors wanted to discuss (with the larger medical community) “whether they already have to speak of a distinct syndrome of social media-induced psychosis.”

And in fact, Dr. Vaughan Bell is one of the top experts to discuss this issue, and I imagine he will address the authors over at Mind Hacks.

But then the Brief Report completely derails with an “experiment” reported in the remaining paragraphs...

The Ben Goldacre Experiment

"This is a path of brotherhood and love" says the new pope, immediately excluding a cool 4 billion people.
— ben goldacre (@bengoldacre) March 13, 2013

Someone (it's not clear who) created a fake account to address whether “Twitter communication responds to changes in communication style.” [NOTE: I'm not sure what this means.]

To test this, a test person created an account and responded to the messages of Ben Goldacre, the maker of the blog http://badscience.net. Our test person responded to a message of Mr. Goldacre about the pope, but Mr. Goldacre did not reply. However, the authors received an answer from an unknown participant, writing "<our username> Cold blooded RT. XXX: I am in the church: <link>." The link led to different Web pages with commercials.

...when the authors followed the link, they were confused about a flood of useless information (commercials). The authors understood that this was a spam message, but this might not be the case for a person who is predisposed to psychosis and, in addition, in a stressful psychosocial situation.

So from this ill-defined, bizarre and staged interaction with a test person, the authors concluded that “Twitter might combine several aspects that could induce or further aggravate psychosis.” In a presumably peer-reviewed publication.3

This is preposterous. Hopefully we will not see “Twitter causes psychosis” headlines any time soon.

ADDENDUM Aug 6 2014: The authors have commented on this post to clarify that they were being deliberately provocative with their title and approach to the topic, but serious about the possibility that the interactive social media aspects of Twitter might have unique qualities in how it could affect those with (or predisposed to) psychosis. Furthermore, the authors are not inclined to generate a new host of DSM-5 diagnoses; in fact, Heinz and Friedel (2014) stated: "The inclusion of non-substance, behavioral addictions poses the danger of pathologizing a wide range of human behavior in future revisions of the classification."

Footnotes

1 However, Bell et al. (2008) showed that individuals with delusions do not always have anomalous perceptual experiences.

2 I imagine “several hours a day” could apply to many individuals without a formal diagnosis of mental illness. I will not deny that Twitter and other forms of social media can have an addictive quality for some people, but the “Twitter addiction” construct is not very useful.

3 Can I put this blog post on my CV?? Here we learn about academic publishing in psychiatry and the propensity to categorize.

Pending approval of departmental funds, the North Dakota School for Social Research is seeking outstanding candidates for its newly developed Interdisciplinary Program in Architecture, Kitchen Design, Sociology of Gender Roles, and Neuroimaging. State-of-the-art Siemens MAGNETOM 7T MRI and 306-channel planar dc-SQUID Neuromag Vectorview MEG facilities available. Start-up funds of $50K provided. Requirement to teach 3 classes per semester, including Statistics, Introduction to Celebrity Chefs, and Advanced Techniques in Optogenetics. The successful Assistant Professor candidate will be expected to obtain NEA funding, publish in high-impact science journals, give a Top 10 TED talk, and negotiate a major book deal before receiving tenure. Experience as a nationally syndicated advice columnist preferred.

...accompanied by a [somewhat] more serious meditation on Neuroetiquette and Neuroculture, which explained that neuroscientists are not taking jobs away from philosophers, sociologists and gender theorists:

I think the neuro-panic among social scientists is overblown. How many philosophers, sociologists, and gender theorists are unemployed because their respective departments have decided to hire neuroscientists instead? How many developmental neurobiologists have applied for this Instructor of Philosophy position at Rochester Community and Technical College? Will a cognitive neuroscientst be able to teach transnational feminism or postcolonial feminism, queer theory, and critical race theory in the Women's and Gender Studies Program at Illinois State University?

Could I have converted all of the above content into a coherent scholarly manuscript that addressed firstly, the pestilent neuro-ization of the academy (and the kitchen),1 and secondly, the reactionary anti-neuro manifesto pushback? Did I even want to? There was certainly no time (or money) for such a project...

Critical neuroscience is an approach that addresses these contested issues surrounding the field of cognitive neuroscience from multiple viewpoints. The aim is to engage neuroscientists with researchers in the humanities and social sciences who deal with the implications of brain-based approaches to fields such as education, law, medicine, social policy, business and with the expansion of neuroscience in the University more broadly. Critical neuroscience encourages collaborative approaches to careful assessments of the status quo, longer-term impacts, potentials and problems of cognitive neuroscience within the laboratory and in the various areas of application. The project has been analyzing methods, technologies and theoretical paradigms, while also drawing on history and philosophy of science, anthropology, sociology and cultural studies, and reaching out to include practitioners from medicine, social policy, counseling and science journalism in order to better understand whether and how neuroscience could have value for these other domains.

Presciently,2 the Editors wanted to “address the visions and challenges surrounding new grand-scale initiatives in neuroscience — including the EU-funded Human Brain Project and a comparable initiative planned in the U.S.”

As it so happens, a mere two weeks ago, the €1-billion HBP was roundly criticized in an open letter signed by 156 neuroscientists (the list of signatories and supporters is now over 700):

...the HBP has been controversial and divisive within the European neuroscience community from the beginning. Many laboratories refused to join the project when it was first submitted because of its focus on an overly narrow approach, leading to a significant risk that it would fail to meet its goals. Further attrition of members during the ramp-up phase added to this narrowing .... including the removal of an entire neuroscience subproject and the consequent deletion of 18 additional laboratories...
. . .

In this context, we wish to express the view that the HBP is not on course and that the European Commission must take a very careful look at both the science and the management of the HBP before it is renewed. We strongly question whether the goals and implementation of the HBP are adequate to form the nucleus of the collaborative effort in Europe that will further our understanding of the brain.

A flurry of press and blog coverage ensued, followed by a bigwig defense in New Scientist and an official statement [PDF] from the HBP. Although it's clear there are fundamental differences of opinion about a massively optimistic and expensive attempt to model the human brain, organizational issues of power and control are key as well:

The nixed subproject, called Cognitive Architectures and headed by French neuroscientist Stanislas Dehaene, represented all the neuroscience in Europe that isn't working on a molecular or synaptic level, says Zachary Mainen of the Champalimaud Centre for the Unknown in Lisbon, one of the authors of the letter. HBP “is not a democracy, it’s Henry’s game, and you can either be convinced by his arguments or else you can leave,” Mainen says.

Ethnographic studies of neuroscience knowledge can potentially offer insight into the relationship between the everyday of scientific practice and reasoning on the one hand and the political and moral economy of science on the other, as well as encouraging conversation between the social and biological sciences, as this special issue aims to do.

In this article we consider the rationale of the RDoC and what it reveals about implicit models of mental disorders. As an overall framework for understanding mental disorders, RDoC is impoverished and conceptually flawed. These limitations are not accidental but stem from disciplinary commitments and interests that are at odds with the larger concerns of psychiatry.

But that's the problem with a multiplicity of specialized viewpoints in academic publishing. Maybe someone (the Editors?) can host a series of interdisciplinary blog posts that are comprehensible to a broader audience?

. . .
Friend, are you troubled by persistent waking blackouts? Do you tremble and shudder and flicker out of consciousness when asked to recall basic facts about your acquaintances? Does your right eye fill with blood whenever you have to try to remember your PIN? Let Lumosity patch over those mysterious missing blank spots in your sick and addled mind.

“Lumosity: Improving your brain through the science of neuroplasticity, but in a way that just feels like games.”

Lumosity: you can trust us. It doesn’t hurt. It’s normal. It feels normal. Good and normal. Just like a game. Won’t feel a thing. It’s normal, and you’re normal, and your brain is working better now than it was before. Before was bad. Now is good.

In reality, though, it's hard to imagine two world views more completely out of step than Neuroscience and the bizarre set of beliefs known as Scientology. {floating tone arms, anyone??}

In fact, Scientology is quite vehemently anti-psychiatry and anti-neuroscience. Many of you might remember Tom Cruise's condemnation of Brooke Shields for taking antidepressants to treat her postpartum depression, to which Shields replied: “Tom should stick to saving the world from aliens and let women who are experiencing postpartum depression decide what treatment options are best for them.”

The stance against psychiatric medication goes much further than that: they would like to eliminate NIMH, the major U.S. funding body for biological psychiatry and mental health research. The Secrets of Scientology site maintained by Carnegie Mellon Computer Science Professor David S. Touretzky has covered the sect's excesses for many years, including in a poster presented at the 1998 Society for Neuroscience meeting:

Opposition to Mental Health Research

Scientology demonizes the mental health professions in part because psychology and psychiatry are Scientology's main competitors. But another reason is that all cult groups need an external enemy to rally against. Scientologists are taught that modern psychiatrists still use lobotomy and electroshock treatments to dominate and control their patients.

Despite this, Scientology started out with a materialist model of the mind before it was derailed (perhaps by founder L. Ron Hubbard's alcohol and drug addiction). As Prof. Touretzky explains:

In 1950 Dianetics presented a purely materialistic view of the mind as a simple computer, with frequent references to "memory banks", "circuits", and data recording. The mind was implemented by the brain, and memory was a product of a cellular recording mechanism. Hubbard did not rule out the possibility that psychic phenomena such as ESP or telepathy might some day be demonstrated, but they played no role in Dianetics.

With the introduction of past lives, Hubbard switched from a materialist to a dualist conception of mind. In Dianetics, the "I" that looked at mental image pictures was the analyzer. In Scientology the "I" is the thetan, a spirit, that moves from one body to the next, carrying its reactive mind along with it. And in advanced Scientology auditing, subjects are instructed to communicate with their body thetans "telepathically", not verbally.

The scientific trappings of Scientology extend even to instrumentation: a skin galvanometer called an E-meter (electropsychometer) is said to allow an auditor (therapist) to observe the creation or destruction of "mental mass'' by reading the needle movement.

According the Church of Scientology's own materials, however, the E-meter is used by auditors to locate areas of spiritual distress or travail:

The E-Meter measures the mental state or change of state of a person and thus is of enormous benefit to the auditor in helping the preclear locate areas to be handled. The reactive mind’s hidden nature requires utilization of a device capable of registering its effects – a function the E-Meter does accurately.
. . .

When the person holding the E-Meter electrodes thinks a thought, looks at a picture, reexperiences an incident or shifts some part of the reactive mind, he is moving and changing actual mental mass and energy. These changes in the mind influence the tiny flow of electrical energy generated by the E-Meter, causing the needle on its dial to move. The needle reactions on the E-Meter tell the auditor where the charge lies, and that it should be addressed by a process.

Different needle movements have exact meanings and the skill of an auditor includes a complete understanding of all meter reactions.

Wow, that is true scientific precision. Impressive, now isn't it? Even the most computationally sophisticated cognitive neuroscientists don't claim to read the hidden mind's reactive nature using multivoxel pattern analysis (MVPA) of fMRI data. Or do they?

“It appears that the human brain generates a special code for the entire valence spectrum of pleasant-to-unpleasant, good-to-bad feelings, which can be read like a ‘neural valence meter’ in which the leaning of a population of neurons in one direction equals positive feeling and the leaning in the other direction equals negative feeling,” Anderson explains.

Call it priming by Ortberg if you will, but terminology like 'special code', 'entire valence spectrum', 'leaning in one direction/the other direction', and 'neural valence meter' sounded a little cult-like to me...

Thursday, July 10, 2014

In the 2000s, enthusiasm was high that a novel class of drugs would reach the market as blockbuster treatments for psychiatric disorders. These drugs act on receptors for a group of neuropeptides known as tachykinins (or neurokinins). These peptides — substance P (SP), neurokinin A (NkA), and neurokinin B (NkB) — function as neurotransmitters or neuromodulators in the central nervous system, but are quite different from the usual monoamines targeted by current psychotropic medications prescribed for schizophrenia, depression, and other mental illnesses.

The tachykinin receptors (NK1, NK2, NK3) have varying affinities for the different peptides, being greatest for SP, NkA, and NkB respectively. A series of clinical trials with NK1 antagonist compounds (i.e., SP blockers) was conducted as potential treatments for major depression, generalized anxiety disorder, alcohol craving, and post-traumatic stress disorder (PTSD). Substance P is released during times of increased stress and localized in brain regions implicated in the stress response (Ebner et al., 2009), so the idea was that dampening the effects of SP would lead to symptom amelioration in these disorders. However, except for some mildly promising results in stressed alcoholics, the trials were disappointing in patients with generalized anxiety and PTSD. Results were mixed in major depression. But those trials, with a GSK compound called orvepitant, were terminated to due serious adverse events (seizures) in several patients.

In contrast, the most promising target for schizophrenia seemed to be the neurokinin 3 (NK3) receptor. This was because of prominent expression on the midbrain dopamine (DA) cells implicated in the pathophysiology of schizophrenia, and because selective NK3 antagonists can block NkB-induced excitation of dopamine neurons (Spooren et al., 2005). The original “typical” antipsychotic medications are DA antagonists, which can have untoward side effects with chronic use. Because NK3 antagonists lack the major extrapyramidal and metabolic side effects of typical and atypical antipsychotics, they were heralded as “the next generation of antipsychotics” in 2005.

In October 1999, Lehman Brothers predicted that the probability of the product reaching the market was 10%, with a possible launch in 2003 and potential peak sales of US $200 million in 2011.

However, Sanofi-Aventis stopped any further development of osanetant in 2005.

(2) The NK3 antagonist talnetant was under development by GlaxoSmithKline, with several clinical trials conducted between 2002 and 2005. But it too was discontinued (in 2007).

In other words, these drugs have not lived up to their original promise as novel treatments for schizophrenia.

“Repurposing” of Drugs

“We should continue to repurpose treatments and to recognise the role of serendipity,” said Geddes and Miklowitz (2013) in a recent review on new treatments for bipolar disorder. Although the article did not hint at any impending pharmacological breakthroughs, the idea that existing drugs can find new indications is especially pertinent in this era of shrinking investment in neuro/psych drug development.

Sometimes the serendipity and repurposing comes from mechanistic preclinical studies that can then be retranslated back to the clinic. Jumping ahead to that possibility, a press release from Emory declares:

Scientists at Yerkes National Primate Research Center, Emory University have identified a drug that appears to make memories of fearsome events less durable in mice.

The finding may accelerate the development of treatments for preventing PTSD. The drug, called osanetant, targets a distinct group of brain cells in a region of the brain that controls the formation and consolidation of fear memories.
. . .

“Potentially, drugs that act on this group of cells could be used to block fear memory consolidation shortly after exposure to a trauma, which would aid in preventing PTSD,” says Kerry Ressler, MD, PhD, professor of psychiatry and behavioral sciences... “PTSD is unique among psychiatric disorders in that we know when it starts – at the time of the trauma. Finding ways to prevent its development in the first place – in the emergency department or the battlefield - is an important and exciting avenue of research in this area.”

NkB and the Consolidation of Fear Memories

A new study in mice found that osanetant could block the consolidation of fear memories when administered within a narrow time window (Andero et al., 2014):

Notably, when osanetant is dosed from 30 min before auditory FC [fear conditioning] up to 1 hr after training, it does not affect fear acquisition but impairs fear memory consolidation as shown by decreased freezing in the fear expression test.

Modified from Fig. 4 (Andero et al., 2014). G:Osanetant given immediately after FC impaired fear memory consolidation in mice that had been previously exposed to a traumatic stress as shown by reduced freezing in the fear expression test, ∗p ≤ 0.05. n = 8 per group.

The starting point of this study, however, was not to test the effects of osanetant on the formation of fear memories. Rather, Andero et al. (2014) began by casting a wide net in search of genes that are regulated during fear conditioning. They found that the Tac2 gene (TACR3 gene in humans) is regulated during fear memory consolidation, specifically in the central nucleus of the amygdala (a “fear learning central” of sorts).

Furthermore, increased expression of the Tac2 gene, NkB peptide, and activation of Nk3R may be involved in stress sensitization and overconsolidation of fear. In contrast, genetic silencing of Tac2-expressing neurons impairs fear consolidation. Blockade of this pathway may provide for a novel therapeutic approach for disorders with altered fear learning such as PTSD.

The clinical potential of this finding is not lost on the authors. If given shortly after a traumatic event (e.g., in an emergency room or combat situation), it's possible that osanetant could reduce the emotional potency of trauma memories:

Finally, one of the most interesting aspects of our data is the potential use of the Nk3R antagonist osanetant as a pharmacological agent to block fear memory consolidation shortly after exposure to a trauma. Additionally, we found that osanetant prevented the upregulation of the Adcyap1r1 gene, which encodes the PAC1 receptor. The PACAP-PAC1R pathway is involved in PTSD, fear conditioning, amygdala excitatory neurotransmission, and stress. All this could be relevant in PTSD prevention since it has previously been found that osanetant is safe in humans, although additional preclinical studies, such as those described herein, are needed first to establish the mechanisms involved. This gives our findings an exciting potential approach to translation to human patients.

This study also provides a perfect example of NIMH's new mandate for specifying a hypothesized mechanism of action for interventions that will be tested in funded clinical trials. Does peri-trauma osanetant (vs. placebo) reduce later development of PTSD symptoms and attenuate amygdala activation to trauma script-driven imagery in fMRI? Is TAC3 gene expression altered in primate models? [The distribution of Nk3R likely differs between mice and primates.] Are there declines in PACAP blood levels in traumatized individuals given osanetant (vs. placebo)? Are there longer-term effects on methylation of ADCYAP1R1 in peripheral blood? These latter measures are biomarkers of an abnormal stress response in PTSD that are currently studied by the Ressler Lab.

At any rate, NIMH Director Insel might as well hand over the money right now...

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.